Summary of Work: These studies identify critical target genes and alterations in genes that may be important in chemical carcinogenesis. Genetic alterations in oncogenes (eg.-ras, beta-catenin) and tumor suppressor genes (eg. - p53 and p16) from rodent tumors induced by certain carcinogens and from human cancers of individuals exposed to environmental agents are being characterized in order to understand mechanisms of chemical carcinogenesis. In one set of investigations beta-catenin mutations are being identified in chemically induced mouse liver tumors. Antraquinone, and oxazepam, caused a significant increase in mouse hepatoblastomas, a more malignant form of hepatocellular carcinoma and a rare tumor in untreated mice. Beta-catenin mutations were identified in all these tumors examined. Beta-catenin protein accumulated in the cytoplasm and nucleus of the hepatocytes. These results are different from those in hepatocellular neoplasms in which the beta-catenin accumulated only along the cell membranes in those tumors with mutations. Identification of other proteins that interact with beta-catenin in liver is now being studied. We are also continuing our study to identify mouse lung tumor susceptibility genes that may have relevant human homologs, and we are concentrating on the Par2 locus on chromosome 18. Also, we are studying methylation of cancer genes such as the telomerase hTERT gene and p16. As part of the environmental genome project we have identified polymorphisms in the human p16 gene and found that some of these in a bladder cancer case/control study may be associated with disease susceptibility (p=.1) - DNA, Genes, Genetic Markers, Lung, Mice, Inbred Strains, Nucleotide mapping, Oncogene Proteins, Smoking, Bladder Neoplasms